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Synaptopathy and Pathogenesis in Frontotemporal Dementia: Role of CYLD

Award Number: R01AG082478
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Synaptopathy and Pathogenesis in Frontotemporal Dementia: Role of CYLD - Frontotemporal dementia (FTD) is the leading cause of dementia before the age of 60 and the second most common form of dementia overall after Alzheimer’s disease (AD), and there is no cure. FTD is caused by focal but progressive atrophy of frontal and/or anterior temporal cortices that leads to changes in personality, apathy, loss of empathy, disinhibition, and language disability at early-mid stages, and general memory and cognitive deteriorations requiring a full-time care at later stages. Consistently, it is thought that early prodromal synaptic and circuit dysfunctions underlying behavior impairments may precede massive late- onset neuronal cell loss and disability. However, molecular mechanisms underlying FTD-associated synaptopathies that contribute to disease initiation and progression are not well understood. FTD is linked clinically, pathologically, genetically, and mechanistically to amyotrophic lateral sclerosis (ALS). Up to 50% of FTD are familial and associated with mutations of at least 15 genes of diverse functions. Remarkably, at least 10 of these genes are involved in autophagy, which has emerged as a central mechanism in FTD/ALS. However, it remains enigmatic how autophagy is dysregulated in FTD/ALS and how exactly autophagy dysfunctions cause the diseases, presenting a major hurdle and knowledge gap in development of autophagy-based therapeutic strategies. Recently, a gain of function mutation in the CYLD gene is identified in FTD/ALS patients, placing CYLD as the newest member of the FTD/ALS-causing gene family. CYLD encodes a Lys63-specific deubiquitinating enzyme and interacts with several FTD gene products, including p62/SQSTM1, Optineurin, and TBK1, suggesting a potential role for CYLD in autophagy related to FTD. CYLD is best known as a tumor suppressor linked to familial cylindromatosis and immune signaling, but its roles in neurons and synapses are poorly understood. Our published and ongoing studies indicate that CYLD is an abundant Lys63-specific synaptic deubiquitinase that has a major role in synapse maintenance, function, and plasticity through regulation of neuronal autophagy. The goals of this R01 application are to define the molecular details and functional consequences of CYLD-dependent autophagy in synapse remodeling (Aim 1), to characterize a newly generated inducible and reversable transgenic mouse model carrying the FTD-causing mutation CYLDM719V in FTD pathogenesis (Aim 2), and to investigate the pathogenic role of CYLDM719V in FTD and explore therapeutic strategies in human induced pluripotent stem cell (iPSC)-derived cortical neurons (Aim 3). Our study represents the first attempt to investigate the role of a new disease gene in FTD pathogenesis. The proposed studies are fundamentally important and highly significant because they have the potential to uncover novel pathogenic mechanisms and treatment strategies for FTD and related neurodegenerative diseases.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $804,625 )
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Aging Research	000	2	6/25/2026	EXTENSION WITH OR WITHOUT FUNDS	$804,625
														Subtotal = $804,625

Grand Total All Awards = $804,625

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Synaptopathy and Pathogenesis in Frontotemporal Dementia: Role of CYLD

Award Number: R01AG082478

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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